Hepcidin Agents Set to Improve Polycythemia Vera Care

Protagonist Therapeutics earlier this month reported positive results from its phase III VERIFY study of hepcidin mimetic rusfertide for the treatment of polycythemia vera (PV).  This marks an important milestone in bettering the care of PV patients as it showed a reduction in the need for phlebotomies that, importantly, was further accompanied by a measurable increase in quality of life. Notably, this did not come at the cost of a greater risk of developing cancer and other side effects such as fatigue that current standard of care agents suffer from.

Subsequent to the release of the VERIFY results, Ionis Pharmaceuticals licensed global rights to sapablursen to Japanese Ono Pharmaceuticals for $280M in upfront.  

Mechanism of action

Similar to synthetic peptide rusfertide, the RNaseH antisense sapablursen aims to increase hepcidin pathway activity by facilitating its  release from the liver.  This can be achieved by knocking down its negative regulator TMPRSS6.  As a master regulator of global iron uptake, storage, and dynamics in the body, hepcidin suppresses the overproduction of red blood cells (erythrocytosis) by restricting iron supply to the bone marrow.  It is the overabundance of red blood cells in circulation and subsequent viscosity that leads to an increased risk of thromboembolic events.  Night sweats, abdominal discomfort, and bone pain are some of the other consequences people with PV suffer from.

The expected life expectancy from diagnosis, typically around the age of 60, is about 20 years.  In about 10-15% of cases, PV progresses to myelofibrosis which carries a poorer prognosis.

Current standard of care

The first-line treatment for PV is ‘blood thinning’ aspirin in addition to bloodletting (phlebotomy) in a procedure that is essentially the same as when you donate blood.  The goal here is to get the fraction that red blood cell occupy in the blood to below 45%.  This is considered to reduce the risk of thromboembolism by 4 fold compared to having a hematocrit value of 45-50%.  The main side effects from phlebotomies is fatigue and general iron deficiency.

When phlebotomy is not enough, or when you are above 60, cytoreductive therapy is indicated.  The typical reason for red blood cell overproliferation in PV is an acquired mutation in the JAK2 gene (V617F)  in hematopoietic cells leading to increased cytokine signaling.  Blood cell lineages other than the erythropoetic one may also be affected.  Second-line agents (used in combination with bloodletting) aim to inhibit subsequent cellular proliferation.

Unfortunately, second-line agents are generally blunt instruments that carry a lot of safety and tolerability baggage.  

First off is hyroxyurea which is, hold on, a DNA synthesis and repair inhibitor and, unsurprisingly is recognized to cause cancer, especially non-melanoma skin cancer.  Add to this the nausea and immune dysfunctions to mention only a few of the other side effects.  I get it: small molecule and cheap, but give me a safer, alternative medicine (and since we are at it, HU is a reminder of all the widely described carcinogenic small molecule drugs and we are agonizing about genome editing agents with mutation rates well below natural sunlight). 

Next is interferon.  Anybody following the hepatitis B virus treatment field knows that this is a very poorly tolerated agent leading  to depression and flu-like symptoms causing patients to frequently stop taking the medication.

Ruxolitinib, a JAK2 inhibitor, is certainly an advance in the cytoreductive approach in PV as it targets the root cause: JAK2 activity.  This, however, also means an increase in the risk of infections (due to suppression of immune cell lineages) and, once again, non-melanoma skin cancer.  Approved for myelofibrosis already, it will be important to see whether its use in PV can also inhibit the progression to myelofibrosis.

Role of hepcidin agents

Due to the safety and tolerability issues noted above, the hepcidin pathway agents should be well positioned to grab a major share of the second-line treatment market.  In addition to not showing an increased rusfertide-related cancer risk or other major safety issues, VERIFY demonstrated that patients actually felt better on the drug.

In some patients, weekly subQ injections eliminated the need for phlebotomies altogether as more than 76.9% on the drug did not qualify for it during weeks 20-32 compared to  32.9% on placebo.  72.8% did not undergo a phlebotomy for the entirety of the primary observation period of the study (week 0-32) compared to only 21.9% on placebo.  

Importantly, the ~300 study participants could be on cytoreductive background therapy.  This may also explain that the mean number of phlebotomies during weeks 0 to 32 for those on placebo was just 1.8, i.e. in line with a regular blood donor.  Adding rusfertide reduced this to 0.5.  

 

PK/PD comparison of hepcidin agents

In addition to the difference of mimicking hepcidin versus inhibiting an inhibitor of hepcidin, another important differentiator is the PK/PD profile of the two approaches differ.  Since peptides typically do not last long in circulation, rusfertide needs to be given weekly with more than 10x differences in peak-to-trough levels.  By contrast, both the Ionis antisense (sapablursen) and Silence Therapeutics SLN124 (divesiran) RNAi TMPRSS6 knockdown agents lead to sustained 3-5 fold increases in endogenous hepcidin depending on dose and dose frequency.

In a study in PV patients, SLN124 led to a more than 10x reduction in phlebotomy frequency compared to the run-in period, although this difference may be more moderate in a placebo-controlled study similar to the Protagonist experience.  In any case, my base case is that efficacy in terms of phlebotomy frequency will turn out to be similar between the two approaches with the more sustained, physiological increase in endogenous hepcidin possibly paying dividends over the longer term.  The reduced drug administration frequency (monthly subQ likely for sapablursen, q6w currently for SLN124) would also favor the oligonucleotide options.

Ionis has been more secretive about the performance of IONS-TMPRSS6 in PV.  They did, however, disclose in an investor presentation that during the partnering process, Ono Pharmaceuticals and other competing companies got to see those data. Based on comparable hepcidin elevations in human volunteer studies, I would expect phlebotomy and other efficacy endpoints to be roughly on par with what Silence Therapeutics has seen, although the 9mg/kg cohort with SLN124 could set a new benchmark if confirmed in a larger study.

Additional Market considerations

There is considerable interest in developing next-generation PV therapeutics.  This is also illustrated by recent deal activity in the space.  In January 2024, Takeda Pharmaceuticals paid $300M upfront to Protagonist for 50:50 US co-development and co-commercialization rights and exclusive ex-US rights following the successful completion of phase II studies.  At the time, rusfertide peak sales were projected to be in the $1-2B range.

This week, another Japanese pharmaceutical company, Ono, obtained full rights to sapablursen from Ionis for $280M in upfront following full enrolment of a PV phase II study, a deal that was likely informed by the rusfertide results.  Though enhanced milestone payments compared to the Protagonist-Takeda deal may somewhat compensate for the lower upfront consideration, the deal indicates that the estimates for the market potential for the hepcidin entrants either have come down or that this market is now expected to be divided up between more players than initially envisioned.

Clearly, the US, with a patient population of 100-150,000, will be the major source of expected profits.  Similar to the hereditary angioedema (HAE) space, similar efficacy, but much better safety, tolerability, and convenience of the new HAE therapeutics have grown that into a multi-billion dollar market despite the availability of cheap alternatives like androgens and a small patient pool of at most 10,000.  

Androgens, however, are still widely used outside the US, even in wealthy countries like Singapore, and unlike HAE, PV is largely diagnosed in older people.  This means that reducing the number of annual phlebotomies by 2 will unlikely justify a $200,000 price tag.  To justify that, hepcidin pathway agents need to have robust phlebotomy-lowering activity in the absence of any other current second-line agents (remains to be seen in the full VERIFY dataset) in addition to demonstrating improved measures of well-being as was demonstrated in VERIFY.  

Disclosure: SLN124 is the core asset of Silence Therapeutics of which I currently own shares.

Proposing Complement C3 RNAi for Treating COVID19

Whereas my last blog considered lung-targeted RNAi for addressing COVID19, this entry will look at what a liver-directed RNAi approach could do for the disease.  It is in the liver that RNAi Therapeutics have proven to be extremely potent.  Moreover, it is amenable to subcutaneous administration and therefore appropriate for the current pandemic.

It has quickly become apparent that in a subgroup of patients COVID19 is associated with liver complications.  Managing these with gene silencing of resident liver proteins may be possible in theory and could be contemplated.  More interesting, however, would be intervening upstream of the liver in the respiratory tract.  

It is reported that it is an overactive (innate) immune system rather than cellular damage (cytopathic) by the virus itself that can cause the virus to be fatal.

And when it comes to an immune approach with RNAi at the moment, the complement pathway, many components of which are predominantly expressed by the liver and secreted into circulation comes to mind.

Interestingly, a relatively recent paper (Gralinski et al, 2018) in a mouse model of SARS-CoV-2-related SARS has shown that genetic complement C3 knockout lessened lung damage and overall health as measured by body weight.  This was associated with a reduced influx of neutrophils which are the carpet-bombers of the immune system.

The next question to be asked is that since RNAi gene silencing is not instantaneous but takes time to manifest, whether such intervention would be timely enough in a given patient.  For this, my assessment is that it should be possible based on the pharmacodynamics of a C3 RNAi in development by Silence Therapeutics (SLN500) and Mallinckrodt IF the disease can be diagnosed in time.

Accordingly, it took about 4 days for robust C3 silencing in mice which compares to the about 7-10 days it takes for SARS-CoV-2 to move from the upper respiratory tract (as manifested e.g. by throat pain) to the lower lungs where the critical battleground is.

These are extraordinary times and I believe this approach should be considered.  Besides Silence Therapeutics and Mallinckrodt, Alnylam, and Dicerna (in partnership with Alexion) are also working on RNAi for the complement system.  A monoclonal antibody approach may also be envisioned and could have advantage of a faster onset of action, but may lag in development timelines.

One Pitfall to Look Out for in RNAi Therapeutics

RNAi Therapeutics have turned the corner to being a generally accepted drug modality.  Following years of ridicule and benign neglect, the industry just celebrated the FDA approval of a 2nd drug, Givlaari for the treatment of acute hepatic porphyria. This was followed in short order by the $9.7B acquisition of The Medicines Company by Novartis for its cholesterol-lowering RNAi drug candidate, Inclisiran, a harbinger for how RNAi medicines will change the game in cardiovascular risk management.

Amid all the understandable investor excitement, it is probably a good time to reflect on the potential pitfalls as we move into a world where RNAi Therapeutics dominate liver-related diseases and advance into new big areas such as the CNS and ocular disease.  Remember, investor, it takes one safety event for the most highly valued programs like HBV RNAi candidate AB-729 by Arbutus Biopharma, Arrowhead Pharmaceutical’s ARO-AAT, or the Lpa program by Silence Therapeutics to decimate your investment by half or more.

Off-targeting safety, off-targeting safety, off-targeting safety

When the discovery of RNAi was rewarded with the Nobel Prize in 2006, the Andy Fire and Craig Mello hammered home a message that would resonate for the years to come: to make RNAi Therapeutics, it’s all about the delivery!

Delivery, delivery, delivery

But as the liver has been conquered and the industry is chewing on a number of liver-related therapeutic opportunities and opening up opportunities in new areas, we still have to fully understand the odds of seeing program failures due to the difficult to predict consequences of off-targeting.

Off-targeting is the moderate knockdown of sometimes dozens of genes sharing sequence homology to the target gene.  This was shown over a decade ago and soon thereafter shown to be addressed by using simple modification strategies.

This, however, was at a time when the delivery mantra was practiced and nobody wanted to risk reducing knockdown efficacy by simultaneously considering off-targeting in their RNAi trigger designs.  I was therefore upset, as it turned out rightfully so, that Alnylam let Nastech essentially go bankrupt a decade ago when it should have acquired rights to Nastech's then industry-leading off-target-mitigation technology.

Alpha-1 Antitrypsin as testbed

Alnylam would have to pay dearly for its pride in never treating a smaller competitor well, even if it served its own interest, with off-targeting manifesting itself in markers of liver toxicity in first-generation clinical programs like chronic HBV and alpha-1 antitrypsin-related liver disease.

These two indications, unlike the now approved AHP indication for Givlaari which addresses symptoms outside of the liver, represent the most exacting off-targeting challenge as they affect liver health directly and any further exacerbation of liver stress should be avoided.  

As a result, Alnylam dug out the old off-targeting literature and in their incarnation added a GNA modification at position 7 of the guide strand while, for experimental purposes, leaving the rest of the first-generation molecule unchanged. Translational science at its best (!) and the industry can be thankful for it.

Indeed, for both the ESC+ chemistry ALN-AAT02 and ALN-HBV02 no liver enzyme elevations (above 3x ULN) were observed in 49 subjects tested, whereas 3 of 33 had such elevations with the ESC-only versions.

In Arrowhead’s case, there also were no ALT elevations >3x ULN.  However, 3 treatment-emergent grade 1 ALT elevations not exceeding 2x ULN were reported in the 28 normal healthy volunteers receiving ARO-AAT.  I am curious to see the individual time curves and the doses at which they occurred.  It is certainly an area to watch for that program as it only now moves into patients. 

Add to this considerable uncertainty about patient selection, dose and duration required to have an impact on AAT liver disease, increasingly analysts topping their price targets by the day may have to re-think how they value this program (see disclosure below).

Further behind, we have to see how Silence Therapeutics and Arbutus have addressed off-targeting with first data expected in 2020.  While Silence has avoided indications directly affecting liver health (iron overload, cardiovascular disease), Arbutus with its HBV indication will have a steeper hill to climb, although the pay-off for investors in this $80 market cap company should be considerable should it climb it come Q1 2020.

Personally, my guesstimate for non-optimized GalNAc designs would be a 50% chance of off-targeting success, also depending on preclinical vetting (after all, the very clean $9.7B Inclisiran is such a design); a 85% off-targeting success for optimized designs. 

Disclosures: long Silence Therapeutics, Arbutus Biopharma; short Arrowhead Pharmaceuticals; no position in Alnylam.

Review of Recent RNAi-Related Developments

The last 2 weeks have been busy ones in the lands of RNAi Therapeutics.  Here, I would therefore like to offer my take on the most important developments.

Alnylam’s Primary Hyperoxaluria Drug Breezes Through Clinic

With 20 subjects on Lumasiran, a GalNAc-RNAi targeting glycolate oxidase, for a median of 7 months, the investigational treatment for type I primary hyperoxaluria (PH1) ismore and more looking like a solid drug.  If the data presented last week at a Paediatric meeting in Turkey hold up in another 30 patients, it should fly through approval onto the market by the end of 2019.

While the relatively small numbers in each cohort has caused a bit statistical noise, it seemed like 3mg/kg monthly gives you an advantage over 1mg/kg monthly or 3mg/kg monthly in terms of the key biomarker urinary oxalate.  Interestingly, the company has chosen 3 times 3mg/kg monthly as the loading dose regimen in the now ongoing pivotal ILLUMINATE-A trial to be followed by dosing every 3 months. , the initiation of which the company has just announced.    

The core double-blind portion of the trial runs for only 6 months, so I am a bit puzzled how much the trial can inform on the value of the loading dose regimen and whether quarterly maintenance doses are sufficiently effective.   In any case, the trial design apparently was blessed by the FDA (incl. the urinary oxalate lowering primary endpoint), so surely they will know (e.g. based on preclinical animal data).

Regarding the competition with the primary hyperoxaluria drug candidate from Dicerna, the approximately 2/3 lowering of urinary oxalate and essentially all patients getting into a range considered safe and an unremarkable safety profile sets a high hurdle for the upcoming data presentation of DCR-PHXC at ASN later this month.

Arbutus HBV-RNAi Drug About to Die   

Yesterday, Arbutus provided an update on its LNP-enabled RNAi drug candidate for the treatment of chronic HBV (ARB-1467) and it does not bode well.  Similar to most other drug candidates attempted and barely tried, ARB-1467 should be canned in the not-too-distant future. 

In a combination study testing ARB-1467 in chronic HBV patients on nucleoside reverse transcriptase inhibitor tenofovir, probably only 1 in 6 patients hit a pre-defined criteria in terms of HBsAg lowering that would allow the patient to then receive immune booster PEG-Interferon.  The not very forthcoming revelation and the fact that the data was mentioned even after dropping another shoe that its small molecule HBV RNA destabilizer is also biting the dust makes it clear that not even the company sees much value in ARB-1467.

What an utter disaster this company has been since its inception as a HBV solutions entity.

Arrowhead Early HBV Deal Further Validates

Last week, shareholders in Arrowhead Pharmaceuticals got a lesson in biotech investing as it shares have given up ~1/3 of its value following a nice deal with Johnson&Johnson for the leading HBV knockdown asset in the space, ARO-HBV.

The deal gives Arrowhead a solid $250M in financing, including a $175M upfront fee and a $75M investment in company stock at a premium of ~50% to current trading.  While this avoids an imminent dilutive secondary share issuance- the company had been running low of cash- the ‘up to 15%’ in royalties from future sales of early phase II-stage ARO-HBV is clearly disappointing.  The relatively low royalty despite of it having confirmed strong HBsAg knockdown in patients can be explained with the fact that Arrowhead has avoided bearing the full risk of having to show proof-of-concept of HBV control.  This despite of having earlier paraded results obtained with an earlier DPC-based RNAi candidate (ARC-520) as strong evidence that RNAi can achieve such immune control.

While Arrowhead got punished for playing it safely, it can now focus on commercial home-run indications with highly validated targets and transition to being a broad platform company with a wholly owned attractive lead candidate in ARO-AAT.  Indeed, Arrowhead may emerge as the leading RNAi company as Alnylam, with a market cap ~8x that of Arrowhead, is still burdened by late-stage RNAi drugs with suboptimal specificity.

While humiliating, this serves Alnylam as a good reminder to also value innovation by the direct competition (note: specificity-enhancing technology now adopted by Alnylam has been available for a decade and could have been had for peanuts, e.g. from now defunct RNAi play mdRNA/Nastech).  Fittingly, today long-time archrival Silence Therapeutics issued a press release indicating that Alnylam is playing hard-ball with regard to Silence-owned IP purportedly covering ONPATTRO.

My guess is that Alnylam would rather risk an injunction and deprive patients of a very good medicine than to submit to what appear to me legitimate demands of a competitor.

Akcea’s antisense drug for TTR amyloidosis gets FDA nod

Last Friday, Akcea’s TTR drug TEGSEDI (licensed from Ionis) finally got FDA marketing approval for patients suffering from TTR-related polyneuropathy.  As expected from the delay in the approval process, TEGSEDI’s approval is accompanied by hefty black box warnings highlighting thrombocytopenia and renal risks of the (non-GalNAc) phosphorothioate oligonucleotide.  

Furthermore, the REMS program calls for frequent blood monitoring, essentially negating the claimed at-your-home convenience advantage over competing RNAi drug ONPATTRO.  Add to the poor safety profile clear efficacy disadvantages and pricing at parity with ONPATTRO, ONPATTRO should clearly win out in the marketplace.

Having said that, the TTR community is relatively small and key opinion leaders with relationships to a given drug company tend to support the drugs from the same company.

RNAi Therapeutics Stocks (Part 2)

Having covered the most developed RNAi companies (Alnylam, Arrowhead, Dicerna) yesterday, this blog entry will discuss RNAi plays that are somewhat less established, but nevertheless could represent interesting investment opportunities.

Silence Therapeutics (SLN.L)

This London-listed company is roughly 2 years behind Arrowhead Pharmaceuticals and Dicerna.  Similar to those, Silence has set its sights on exploiting targets in liver hepatocytes using GalNAc conjugate technology.  Its first program targeting TMPRSS6 for iron overload disorders should enter the clinic in the first half of 2019.

The strength of Silence is partly its RNAi trigger IP position which, if the claims stand, should read on Alnylam’s 3-4 drug candidates that could come on the market over the next 2-3 years.  In my opinion, it would take a generous interpretation of what constitutes a ‘pattern’ for LNP-enabled Patisiran to fall under Silence IP, but it is much less of a stretch for the more stabilized GalNAc-enabled Givosiran, Fitusiran, and Inclisiran molecules in late-stage development.

Part of the potential upside could  therefore come from a settlement of the IP litigation that Silence has filed against Alnylam as it could hamper the commercialization of Alnylam's RNAi drug, especially as it ramps up for the launch of Patisiran. 

The reason why such revenues would be meaningful to the company is that Silence is run extremely well in financial terms such that these funds would neatly feed into Silence's operations as it is about to expand clinically all the while minimizing shareholder dilution. 

This, however, could also be viewed as a necessity since it is much more difficult for a London-based company to raise the kind of biotech ‘risk capital’ that allows companies like Alnylam in the US to really press down the gas pedal to pursue a grand vision without killing shareholders.   

Silence Therapeutics is an investment for those that value the pursuit shareholder return instead of mere market cap growth (=management bragging rights).  While I support this strategy, I am still largely on the sidelines as the company needs to address the anemic trading volume which makes it very costly to trade in and out.

RXi Pharmaceuticals (RXII)

Who doesn’t dream of striking it rich overnight?  If so, RXII is the type of stock that in the right biotech environment could be your daily biotech double in the not-so-distant future.

After all, which other biotech with a market cap of ~$15M can boast about 3 clinical data read-outs before year-end and one additional in early 2018?

1) Q4 2017: phase II results dermal scarring (RXI-109)

2) Q4 2017: phase II results warts (samcyprone, non-RNAi)

3) Q4 2017: UV-induced hyperpigmentation results, consumer testing (RXI-231)

4) Q1 2018: phase I/II results retinal scarring (RXI-109)  

It is possible that the first 3 data read-outs could show that the agents are active and well tolerated, but where there will be a discussion about the commercial adoption of these agents in the real world.  Therefore, the real fireworks may occur following the results from the retinal scarring phase I/II trial in early 2018.  Here, the self-delivering RNAi trigger technology is tested for the first time in the eye where for reasons of technical feasibility (more equal biodistribution throughout eye than in the skin) and clinical application I see the most potential for this technology.

Downside risk comes from management that is pitifully ignorant about the workings of the financial markets and shareholder value creation.  If RXi fails to ignite investor interest in the wake of any of these 4 shots on goal, we could well see a continuation of the financial death spiral that has seen RXII lose 98-99% of its value in the last 3-4 years!!!

I own approximately 3% of the outstanding shares of RXII and will try to add on any weakness ahead of data release.

Arcturus Therapeutics (ARCT)

In sharp contrast to RXi, I view management of Arcturus as far more savvy when it comes to the financial markets and building a biotech company of decent size.

Arcturus, which has recently gone public via a reverse merger, has its roots in RNAi technology, largely by copying liposomal delivery technology from Tekmira (now Arbutus) and then licensing related RNAi IP from Marina Biotech.  In light of the Patisiran APOLLO results, you could view the platform as fundamentally de-risked.

In fact, its lead program was an RNAi program to address TTR amyloidosis.   Since then, however, Arcturus has largely re-tooled itself as an mRNA Therapeutics company using LNP delivery technology.  Although its pipeline is not as prolific as that of much-better known Moderna, it appears impressive for a company with a market cap of still less than $100M just as its partnering activities.

Therefore, Arcturus is a bet on a management that can take average science to build a significant biotech as it talks the language of Wall Street and Pharma deal makers.  It was one of my early biotech investment mistakes to undervalue big-mouthed management relative to science. The best science can always be acquired once you have lowered your cost of capital by growing market cap.

I have a starter long position in ARCT as I wait for it to be discovered by larger hedge fund manager.

The final instalment of this series will cover oligonucleotide therapeutics companies Ionis Pharmaceuticals, Wave Life Sciences, Regulus Therapeutics, and Sarepta.

Artificial Intelligence for RNAi Gene Target Discovery Still Early

It’s not every day that you can see a person like chess playing legend Gary Kasparov at a biotech company’s Investors Day.  And if you did, you might wonder whether this was  some kind of stunt.

I was therefore pleasantly surprised to find that Kasparov was indeed a very fitting appearance investor event by Silence Therapeutics this week (for presentation here).  In the 80s, Kasparov apparently gained an edge over the competition by analyzing opponents’ playing habits using ‘big data’ at a time that personal computers were only about to take off.  As a former professional chess player himself, the CEO of Silence (Ali Mortazavi) therefore believes that there similarly must be ways to more efficiently take advantage of the realms of genomic data being generated to gain an edge over the pharmaceutical competition in finding attractive targets and indications for RNAi gene silencing.

Herd mentality

One of the main reasons I used to look down at Big Pharma  with disdain was their herd mentality especially with regard to the targets and indications they are pursuing.  You can bet that if there is general hype around a certain target, or that once a target has been validated for a commercially attractive indication in a clinical proof-of-concept study, almost all Big Pharma companies will be pursuing corresponding programs.

Unfortunately, such herd mentality is not restricted to Big Pharma, but can also be observed in the biotech space (see PD/PD-L1 for cancer etc etc), even in the subsector dearest to my heart: oligonucleotide therapeutics.  Be it TTR, AAT, DMD, or HBV: once there is a compelling therapeutic rationale for pursuing a gene target, multiple companies will be on its case.

It is for this reason, particularly the fear that an Alnylam or Ionis will scorch the earth around these targets, that many companies now delay disclosing the nature of their most promising preclinical programs.  This is remarkable since small biotechs like Dicerna typically rely on disclosure of their of these programs to garner the necessary investor interest.

Target scarcity?

The fact that the lead programs of RNAi therapeutics companies frequently overlap also beckons the question of whether there is a biological scarcity of targets available.  This would be in contrast to Alnylam which have limited themselves to GalNAc-RNAi trigger conjugates for gene knockdown in the liver, claiming- in the flowery languish of its CEO- to be ‘drinking from a firehose of opportunities’ in just the hepatocyte.

To Alnylam’s credit, it has not only duplicated some of the programs initiated by antisense competitor Ionis Pharmaceuticals and that of its smaller RNAi competitors, they have done some of the heavy lifting themselves.  It was e.g. Alnylam that realized the true value of going after transthyretin for TTR amyloidosis and it was Alnylam that selected a target as unorthodox, but promising as antithrombin for the treatment of a protein deficiency: hemophilia (à ALN-AT3/Fitusiran). 

Other companies like Dicerna and Arrowhead Research can also be complimented for unearthing gene target nuggets for orphan indications like primary hyperoxaluria and liver disease due to certain mutations underlying alpha-1-antitrypsin disease.

Mining for targets

I am not concerned about a dearth of suitable targets that could inhibit the continued growth of RNAi Therapeutics.  This is because there are thousands of rare and severe diseases for which there should be straight-forward genetic solutions and because genetic/genomic information continues to explode.  Still, there is certainly tremendous value if you are the first to gain high conviction around a new target and it was the CEO of Silence who bemoaned what seemed to him like an archaic, manual process of sifting through the genetic ideas one by one.

The panel discussion largely cautioned that human curation will remain dominant for the foreseeable future.  I am slightly more optimistic (or pessimistic, depending on your attitude towards AI) and give AI 5 years or so until it will become a more and more compelling means for driving gene target discovery.  This delay relative to areas like the internet is largely explained by the fact that whereas genomic information has exploded, databases that link them to careful, systematic medical phenotyping are still in their infancy. 

In the meantime, some low-hanging fodder for oligonucleotide drug development may come as a by-product of genetically diagnosing rare diseases when often the last hope for getting a grip on a condition is to genome sequence the patient.

There are beneficiaries already from the recognition of the importance of pairing phenotype with genotype databases such as 23andMe which is said to be getting quite a bit interest from pharmaceutical companies and investors. This comes after the pioneer of sifting through genomic/phenomic data for target discovery, deCODE of Iceland, was acquired by Amgen in 2012.  deCODE rose to fame by linking population-wide genetic information to national health-record databases.  I would think that we will see quite a few more similar endeavors linking existing (à nations with a high level of social bureaucracy such as the Nordic countries) or IT-driven newly generated (à Google, wearables) health records to genome and transcriptome databases. 

And as these databases grow and become more intelligent, it will be those that first understand to harness them that will gain a Kasparov-style edge over the competition.  But don’t be afraid: AI should not make human gene target discoverers/evaluators redundant any time soon and their cost relative to the cost of developing drugs is too low.  If anything, they will be needed to make the ultimate decision of whether to pursue a proposed target as each disease is unique and it will take a long time until enough billion-$ clinical experiments will have been run to provide sufficient feedback for the AI to improve.

 Silence Therapeutics: Ready for Take-off

I usually do not attend biotech companies’ Investors Days, but since London is not too far away from home, I took advantage of the proximity to get a feel for how the company has matured. 

Silence Therapeutics has long been a player in the area of RNAi trigger design and IP (see also their claim on Alnylam products), but has struggled to come up with compelling therapeutic programs.  It was as if they never really tried.  This can probably be attributed to them having lacked the personnel with the experience of taking an idea through the clinic and onto the market.

It now seems as if they not only got the technology (à focus on GalNAc-RNAi) to the point of clinical maturity, but also have assembled the management with the skill and will to succeed in developing game-changing RNAi drugs.  First up will be SLN124 targeting TMPRSS6 for iron overload disorders with a projected CTA/IND filing in Q4 2018.

Alnylam’s Scientifically Dishonest GalNAc Claims

Arrowhead Research, as the successor of Mirus Bio, can regard itself as the father of GalNAc-conjugated RNAi delivery.  Accordingly, in 2007, Rozema and colleagues published a seminal paper in which a multivalent polymer-conjugated GalNAc construct was utilized for the hepatocyte-specific delivery of RNAi gene silencing.

In 2015, Alnylam likes to be recognized as the inventor of GalNAc-oligonucleotide Therapeutics, with competitors like Isis Pharmaceuticals and Solstice Biologics playing the roles of copy-cats, and Arrowhead Research failing to get much mention at all.

This, however, is as noted in the introduction far from the truth, and a recent paper on ‘sequentially assembled’ GalNAc-RNAi triggers by Alnylam (Matsuda and colleagues, 2015) is yet another example for how they would like to re-write history to suit their (IP) goals.  History repeating itself you might think after all we’ve been through with SNALP LNP.

Matsuda re-discovering Rozema

Alnylam likes to laugh off Arrowhead’s GalNAc approach by claiming that you need a magic triantennary GalNAc ligand design with highly specific geometry to achieve tight ASGPR target receptor binding and subsequent cellular internalization.  By contrast, Arrowhead Research would be only using monovalent GalNAc which are known, in isolation, to be much poorer ASGPR binders.

The existence of the triantennary design obviously has not evaded Arrowhead Research.  Nevertheless, they have opted for monovalent GalNAcs most likely for their chemical simplicity and therefore reduced cost of goods.

The apparently high cost of triantennary GalNAc synthesis was acknowledged in the Matsuda paper and was said to be the motivation for testing RNAi triggers in which instead of a single triantennary ligand, monovalent GalNAcs were distributed along the RNAi triggers.

Short story short, having GalNAcs conjugated on 3 sequential nucleotides or every other nucleotide did not impact potency much compared to the triantennary 'parent' design.  In other words, the benefit from multivalent binding can be achieved by bringing monovalent GalNAcs together in space.

This, of course, is the same principle behind the Arrowhead approach, where GalNAcs are added to the free amines along a polymer/peptide (an RNAi trigger is just another polymer).  In the case of the melittin-like peptide, I have highlighted the basic amino acids to which GalNAcs are expected to be conjugated:

NH-LIGAILKVLATGLPTLISWIKNKRKQ-COOH

As you can see, towards the C-terminus (right hand side) of the peptide, there is a cluster of 4 positively charged amino acids that is expected to generate a multivalent ASGPR binder (note that 3 and 4 GalNAcs have similar binding affinities).

Shockingly, while masquerading as the inventors of GalNAc Oligonucleotide Therapeutics with statements like these…

‘The triantennary GalNAc ligand was subsequently used for hepatocyte-specific delivery of antisense oligonucleotides and short interfering ribonucleic neutrals (siRNNs) in mice, and anti-microRNA therapeutics in humans, confirming the value of the parent trivalent design.’

…they failed to even cite the Rozema paper and went on to say that now (i.e. for the first time) they were going to test the hypothesis that sequential monovalent GalNAcs could do the same job.  This obviously is a clear case of willful scientific dishonesty in their campaign to re-write GalNAc history.

Silence Therapeutics not even a pimple

While the Matsuda paper is geared towards claiming the sequential GalNAc assembly idea and is an affront to Arrowhead Research, it is also a reminder that Silence Therapeutics has been similarly treated with disregard in Alnylam’s ‘invention’ of ‘enhanced’ GalNAc-siRNAs. 

This is because (like Arrowhead Research actually), Alnylam, at least in essentially all RNAi trigger examples in the Matsuda paper, uses the AtuRNAi trigger design, US patents of which claim 2’-O-methylation every other base with a staggered pattern as it regards the annealed guide and passenger strands.

It therefore looks more and more like Alnylam will have to approach Silence Therapeutics for a license sometime before enhanced GalNAc-siRNAs hit the market (at least 2 by 2020 according to Alnylam’s 2020 guidance), if not ALN-TTRsc already (~2017-8).  If Alnylam will have to approach Arrowhead Research for a license regarding GalNAcs, I do not know, but given Alnylam’s noise, worth paying attention to the intricacies of the various IP estates. 

RNAi Trigger History Revisited as Alnylam Once Again Gets Tough on IP

Last month, Alnylam lectured  Arrowhead Research that they infringed Alnylam's RNAi trigger IP and added that the use of UNAs would not protect companies using them (Tekmira, Arrowhead Research, Marina Biotech, and Arcturus) either.  So as Alnylam is once again trying to intimidate the competition and their investors by claiming that they control RNAi triggers, it might be worth revisiting some RNAi trigger history.  Doing so suggests that in fact they have been one of the egregious infringers of 3^rd party IP themselves and raises questions as to their own freedom-to-operate and validity of IP.

Sirna and Silence Therapeutics early proponents of modified RNAi triggers

The early RNAi days were marked by the competition for RNAi trigger supremacy between star-studded start-up Alnylam and working-class Sirna Therapeutics which had just averted bankruptcy following failed attempts with ribozymes.  Silence Therapeutics was another company that had ambitions to cornering important RNAi trigger IP and like Sirna had a history in failed attempts with oligonucleotide therapeutics.

Due to their prior experiences in nucleic acid-based drug development, it came natural to Sirna and Silence to apply nucleic acid modifications and soon earned a head-start in creating IP related to the use of modified RNAi triggers.  The belief was that in order to endow RNAi triggers with pharmaceutical properties, they had to be modified.

Sounds familiar? If so, then it is probably because this has become Alnylam’s new mantra, too.  Of course, this comes with a 12-year delay and only after acquiring Sirna’s IP estate and a history of claiming that they want their RNAi triggers to be as ‘natural’, i.e. unmodified, as possible, not due to IP limitations, but because of superior performance and considering safety.  In fact, Alnylam has not only been infringing Baulcombe IP for a short while, but also Merck/Sirna IP for probably as long as they were starting to see decent in vivo knockdown results with their highly modified GalNAc-siRNAs.

Although this clearly shows that Alnylam’s publicly claimed control over RNAi trigger IP has simply been a mirage, to their credit they make efforts in eventually gaining access to IP they are glaringly lacking.  Also, while at some point and for some delivery strategies the notion of minimally modified RNAi triggers had its merits, the emergence of RNAi trigger conjugates has increased the value of RNAi trigger modifications.  One might also criticize companies like Sirna/Merck, Silence, and RXi Pharmaceuticals (one of the first practical adopters of highly modified RNAi triggers and conjugates) for standing still instead of developing their initial technologies to their logical conclusion.

A comeback for AtuRNAi triggers?

Silence Therapeutics left a lot of value on the table by limiting themselves to a modification pattern that involves alternating 2’-O-methyls with a 2’-O-methyl-modified base on one strand opposing an unmodified base on the other like in a zipper.  One reason for this limitation was that during patent prosecution, the attempt by Silence Therapeutics to get patents related to modification patterns in general and not limited to 2’-O-methyls failed.

Interestingly, the RNAi triggers in ARC520 that Alnylam lays claim on involve a modification pattern reminiscent of AtuRNAi, only that it is here 2’-fluoro that is the alternating modification (Wooddell et al. 2013).  Also, if you review Alnylam’s recent patent applications (e.g. WO2014089313), alternating 2’-fluoros seems to be Alnylam’s preferred modification pattern, too.  Could it be that these companies were inspired by AtuRNAi trigger design?   

In any case, AtuRNAi and Silence may hold the key to invalidating some troublesome modified RNAi trigger IP by Alnylam by rendering them obvious.  Even more exciting for Silence, albeit unlikely given that the opportunity may have passed is the prospect that Silence could revive some of the more general RNAi modification pattern claims, thereby affecting the freedom-to-operate by Alnylam (and Arrowhead Research).

And welcome to Amy Shuman, former general counsel of Pfizer, to the Board of Directors of Alnylam.

Silence Therapeutics DACC Lipoplexes for Lung Endothelial RNAi Delivery

After having shown for some time now deep and long-lasting gene knockdown in lung endothelial cells, Silence Therapeutics has finally published (Fehring et al. 2014) more detailed chemical and pharmacokinetic information on the DACC formulation.  This formulation could be useful for indications such as cancer involving the lung and acute lung injury.

Chemistry: cholesterol replaces helper phospholipid DPhyPE

Atuplex has long been the workhorse delivery technology of Silence Therapeutics.  Atuplex has been shown to target pretty much all vascular endothelial cells independent of tissue/organ system and enables the company's lead candidate, Atu027 for the prevention of cancer metastasis currently in phase Ib/IIa in combination with gemcitabine in pancreatic cancer.  Unlike the four-lipid formulation pioneered by Tekmira, Atuplex consists of just three lipids:

-          the cationic lipid AtuFECT01 for cell attachment and penetration (proprietary);

-          a pegylated lipid to prevent aggregation;

-          and the helper phospholipid DPhyPE for structural stability.

To my surprise, the DACC formulation contains the same cationic and pegylated lipids as Atuplex.  The main difference is in replacing the helper phospholipid DPhyPE with another helper lipid, in this case cholesterol.  With this change (and some adjustments in the lipid ratios), 40% of the DACC ends up in the lung with the concomitant silencing of genes in resident endothelial cells.

Silence Therapeutics’ strategy of utilizing a given cationic lipid in new lipid combinations therefore stands in contrast to previous efforts by the likes of Tekmira and Dicerna which have focused on the discovery of new cationic lipids to increase potency and the therapeutic index.

Rationale of DACC over Atuplex for lung endothelial RNAi not fleshed out

Although the new research clearly shows that the lung is the most important physical sink for DACC, the study did not investigate whether this translates into a tissue-specific knockdown effect as well [correction 28Jan14: Figure 4 of the paper does show preferential knockdown in endothelial cells of the lung versus other tissues].  This would be an important additional safety-related rationale for using DACC over Atuplex for lung endothelial gene knockdown, especially for target genes that might have critical functions in normal physiology as well. 

Atuplex, in contrast, has previously been shown to mediate lung endothelial gene knockdown, not just in mice (as DACC in this study), but also non-human primates.  What is more, the previous Atuplex studies showed comparable (~70-80%) knockdowns at ~10-fold reduced dosages (0.3mg/kg vs 2.8mg/kg).  It will therefore be important to test whether lower dosages are feasible for DACC knockdown in non-human primates, potentially with the use of slow infusions instead of bolus injections as was the preferred method in the present study.  And as is my pet peeve when it comes to Silence’s delivery technologies, why not attempt them with other, non-AtuRNAi trigger technologies when a factor of 2 could make all the difference in whether you have an acceptable therapeutic window or not.   

It should be noted, however, that unlike Atuplex, DACC appears to have a more reliable dose-response and seems to be tolerated at up to 6mg/kg so I trust that Silence has good reasons for choosing DACC for programs such as acute lung injuries (ALI). Based on the data revealed by the company thus far, it appears that the ALI candidate Atu111 is the prime candidate to be Silence's next clinical development candidate.

Silence Therapeutics to Validate Endothelial RNAi Knockdown in Man

This Monday, Silence Therapeutics held an investor evening in London.  To my surprise, interest in the company and technology was such that 80-100 largely analysts, investors, and fund managers crowded the elegant Victorian-style room at the Royal Institution.  In stark contrast to the quaint setting, the main message of the evening was that the company won’t play it conservatively when it comes to this cutting-edge medical technology and is about to test whether their lipoplex-based delivery technologies can knock down genes expressed in endothelial cells…in Man.

Whereas RNAi Therapeutics have more or less conquered the liver, opening up a whole host of indications to RNAi Therapeutics, despite the apparent accessibility of the vascular endothelial system to delivery and promising animal studies, it has proven a more difficult tissue to firmly establish gene-specific knockdowns.  Part of this technical problem is due to the fact that the vasculature, especially the capillaries which are of most functional importance, is tightly interwoven into the tissues that they supply.   This causes experimental difficulties of obtaining pure endothelial cell populations, a particular concern when genes are also expressed in the more abundant host tissue cells.  Moreover, unlike the liver, proteins (and RNA) expressed in the vasculature are not commonly found in the serum.  The latter is of particular importance in clinical studies where taking appropriate biopsies is either not technically feasible or would be deemed unethical.

Similar to how the clinical demonstration of target gene knockdown in the liver has turned around the fortunes of the likes of Alnylam and Tekmira, Silence Therapeutics also wishes to remove remaining doubts by conducting a second phase Ib/IIa study with lead candidate Atu027, this time not in pancreatic cancer (impossible to obtain adequate biopsies in advanced pancreatic cancer patients), but for head and neck cancer (anticipated regulatory submission in 2014).  Head and neck cancer is one of the few cancers for which the tissue is readily accessible.  And while they are at it, they also will take muscle biopsies to look for PKN3 target repression, and look at a whole slew of other assays, some serum-based, for their ability to assess gene expression in vascular endothelial cells.

In addition to the clinical efforts, I also expect the company to more strongly adopt non-human primates for their delivery studies.  When it comes to liver-directed RNAi, non-human primates have been accepted to be a highly predictive surrogate for performance in humans and one can expect the same to be true for endothelial gene knockdown.

The strategic changes are accompanied by continued corporatere-organization of which the most notable overall change may be the increased clinical focus.  This effort is spear-headed by Dr. Michael Khan who is trained in internal medicine and thus has a good feel for selecting interesting indications of unmet medical need and conducting the appropriate clinical studies.  On the scientific front, the most notable change is the departure of long-time CSO Dr. Klaus Giese (due to family reasons), succeeded by long-time comrade Dr Joerg Kaufmann.

In addition to picking up details like the ones above, such investor events are also an invaluable opportunity to gather insights into the investor base and other people associated with the company.  In that regard, the new CEO Ali Mortazavi has done an remarkable job not only at expanding the technical, clinical, and business development expertise of the company, but also at putting the company in a position to become a sustainable stand-alone biotech company which, if you have followed the fate of UK biotech, is not an easy task.  With Atu027 clinical efforts in high gear and Atu111 for acute lung injury likely to join the clinical pipeline in 2014, the coming period will not only test the organizational skills of management, but also their ability to react to share-price moving clinical events.  Expecting success, Silence Therapeutics is striving for a full listing on the LSE thereby opening up the company to an even larger investor base.        

To learn more about Silence Therapeutics and related events, please follow this link.

Silence Therapeutics First to Advance Systemic Cancer RNAi Therapeutics into Phase II

Among the first crop of systemic RNAi Therapeutics for cancer (see also CALAA01 by Arrowhead and ALN-VSP02 by Alnylam), Atu027 has become the first to officially enter phase II clinical development.  Following the completion of a bridging phase Ib study testing the safety of Atu027 in combination with chemotherapeutic gemcitabine for a treatment cycle of 28 days, Silence Therapeutics announced this week that safety and efficacy of the RNAi-chemo combo will now be more rigorously tested in an expanded phase II study for the treatment of pancreatic cancer.

The bridging study became necessary since in the initialphase I study, the safety of Atu027 was assessed in isolation only.   The press release by the company now suggests that the bridging study testing 0.253mg/kg of Atu027 along with 1000mg/m2 gemcitabine was uneventful since no expansion of cohorts was deemed necessary.  Such an expansion would have become necessary if a dose-limiting toxicity had been observed.   Accordingly, the results are in line with the phase I studies where a dose limiting toxicity was only observed at the 0.336mg/kg dose of this AtuRNAi-lipoplex formulation.

Given that Atu027 is not thought to have a strong effect in terms of directly killing cancer cells, but instead is expected to inhibit metastatic spread, the company believes that it will be clinically most useful in combination with an antineoplastic agent such as gemcitabine in pancreatic cancer.  The choice of pancreatic cancer was probably driven by the high unmet medical need in this indication and it is possible that additional combinations will be explored for a range of other cancers.  Such an expansion of the Atu027 franchise will have to be balanced by the advancement of other RNAi Therapeutic candidates with more straightforward mechanisms of actions to put the company on a more balanced financial footing.

* In addition to the systemically delivered Atu027, two other RNAi Therapeutics for cancer have entered phase II development.  These are the implanted RNAi trigger-eluting siG12D LODER from Silenseed, also for pancreatic cancer, and ex vivo ddRNAi-GMCSF gene therapy combo bi-shRNAfurin by Gradalis for a variety of cancers.

RNAi Therapeutics Companies Cashed Up and Ready to Strike

With the $36M fund-raising last night, Arrowhead Research has become the 4^th publicly traded RNAi Therapeutics company in short succession to cash up for a real shot at drug development success.  The other companies are Tekmira, RXi Pharmaceuticals, and as it was made official this morning, Silence Therapeutics.

The money will be spent on promising drug candidates in the cancer field (TKM-PLK1, Atu027), chronic HBV (ARC520), and scarless wound healing (RXI-109) without having to take dangerous short-cuts or partner the crown jewels prematurely.  Moreover, it will help to advance critical delivery technologies such as DPC, SNALP, and self-delivering RNAi triggers which should provide for non-dilutive partnering opportunities without having to entertain low-ball offers.   

It is notable (and not surprising) that unlike Marina Biotech and Benitec which so far have failed to similarly escape the financing maelstro, Tekmira, Arrowhead and Silence all sport healthy in-house R&D operations.  RXi does not have such operations- yet.  However, they were critical for bringing RXI109 into the clinic on which the company’s ~$80-90M market cap rests.   

The cash infusions should also give the companies, which among them own most of the leading platform technologies, the opportunity to make up for the 20-30 fold gap in valuation to the likes of ISIS Pharmaceuticals (2.3B market cap in antisense), Alnylam (1.5B market cap in RNAi), and Sarepta (1B market cap for a phase II orphan indication).  If monoclonal antibodies are any guide, this will not play out as the winner-takes-all the public markets have it right now.

Below is a quick rundown of the newly cashed-up crop of RNAi Therapeutics companies for those new to the field.

Disclosure: I am long Tekmira and Arrowhead Research. 

Disclaimer: Investments in RNAi Therapeutics carry more risks than you want to know and think about.  The following can only be a very brief teaser for you to start your own due diligence.

Arrowhead Research: In the pursuit of a cure for chronic HBV

Market cap: ~60-70M (of which ~$35M in cash)

Unless Arrowhead Research comes up with a compelling orphan drug application of its technology when it will disclose its second development program in H1 2014, investment success will hinge on the fate of ARC520.  ARC520 is Arrowhead's unique attempt at a functional cure for chronic HBV that will enter clinical development shortly.  I interpret last night’s fund raising in that the IND-enabling tox studies were positive.  The results of these will be critical in determining whether ARC520 can be dosed high enough to safely achieve the type of 90% HBsAg reductions that will be required for that lofty goal.

With cash of around $35M, Arrowhead can now retain full rights to that program at least after value-inflecting phase I proof-of-concept knockdowns have been achieved.  To extend the cash runway beyond the predicted ~2 years, Arrowhead owns the exciting Dynamic PolyConjugate delivery technology, particularly the subcutaneous version and potential new developments for cancer applications.  DPC offers an obvious non-dilutive funding opportunity.

Having slept over the announcement of the PIPE financing which doubles the share count near multi-year lows, I believe it still was a good one in a difficult situation.  Potential partners would have liked to exploit the financial weakness of Arrowhead and the fast-money crowd (think Dawson and Rodman) would have liked to reap risk-free gains from trading around a public offering.  Instead, Arrowhead seems to have found one or more significant investors that share the vision with management.  It is comforting that besides the sweet entry price, no special gifts in the form of warrants and otherwise seemed to have been handed out.  No wonder Arrowhead closed up 13% the day after the financing.

Upcoming catalysts:

  - Determination of maximally tolerated dose in volunteer study with ARC520;

-          - DPC partnering (always on the table);

-          - Modest ALN-TTRsc results would emphasize value of DPC (mid-2013) and may get Alnylam into  play;  

-          - DPC data on cancer (probably H1 2013);

-          - Nominating new development candidate (Q2 2014);

-          - ARC520 viral knockdown results in the Hong Kong trial (H1 2014).

Tekmira Pharmaceuticals: Quality Technology, Quality Financial Management

Market cap: ~$70M (of which ~$40M in cash)

If you are looking for relative stability in RNAi Therapeutics, Tekmira could be attractive.  It was its SNALP technology that enabled the current revival (with well over $300M capital inflows in the industry in the first 4 months of this year) and remains one of the two leading systemic delivery technologies with the value possibly shifting towards oncology indications.  Its leading development candidate, TKM-PLK1 for solid cancers, is about to enter phase II studies and has yielded promising dose-related evidenceof efficacy in phase I. 

The company’s aerosolized LNPs could be an unanticipated windfall for investors, although I have yet to see the all-important safety data.  Its Ebola biodefense program is not valued much by the market, but has been an important stabilizing factor for the company in terms of funding and represents an attractive commercial opportunity in its own right.  

Upcoming catalysts:

-          - TKM-PLK1 data from the expansion cohort (H2 2013);

-          - Design and initiation of phase II studies for TKM-PLK1 (H2 2013);

-          - Follow-up candidate and potentially data for TKM-EBOLA (H2 2013);

-          - Nomination of new development candidate;

-          - $5M milestones each if ALN-TTR02 by Alnylam enters phase III development and Ascletis   initiates a trial in China with ALN-VSP02 for primary liver cancer (both H2 2013/H1 2014);

-          - Partnering of SNALP delivery technology, also for non-RNAi, non-therapeutic applications (always on the table);

       - Monetization of Talon royalties (uncertain timing if at all) 

Silence Therapeutics: A novel cancer approach and strong purchasing power

Market cap: ~150M (of which $30-35M in cash)

Following a remarkable financial turnaround and management reshuffle, Silence Therapeutics has become a force to be reckoned with once again.  Unlike in the early days, it is the product candidates, and not RNAi trigger IP, that is the focus of the New Silence.

First and foremost is Atu027, an endothelially targeted RNAi Therapeutics aimed at preventing cancer metastasis.  The company believes that Atu027 will be most useful in combination with small molecules that aim at killing primary tumor cells and consequently is about to initiate phase Ib/phase II combination trials.

According to the information in the latest financing (which was approved today), a significant investment will be made in building a broader pipeline.  This will take advantage of the company’s three lipid-based delivery technologies: Atuplex (broad endothelial cells), DACC (lung endothelial cells), and DBTC (cells in the liver).  In general, the market cap and cash infusion position the company well to pick up some distressed RNAi and other assets.

Upcoming catalysts:

-          - Initiation of pancreatic cancer combination trial with Atu027 (H2 2013);

-          - Nominating new development candidate(s) (H2 2013);

-          - Pre-clinical data on liver delivery technology (2013);

-          - Partnering, also for non-RNAi, non-therapeutic applications

RXi Pharmaceuticals: Just dermal anti-scarring no more  

Market cap: $80-90M (of which ~$20M in cash)

RXi Pharmaceuticals is the company that popularized the self-delivering RNAi trigger concept.  Unfortunately for the company, it made a critical IP mistake of staying clear of the most potent versions it could have created with its ideas (à dsRNA length).  Furthermore, it seemed that it never was able to get anything into the clinic.

This changed last year with phase I initiation for RXI-109, a potentially superior alternative to Pfizer’s antisense-based dermal anti-scarring candidate.  However, as part of a reorganization, it essentially got rid of its R&D to focus all resources on RXI-109.

As you know, getting rid of in-house R&D is a mortal mistake if you want to be a platform-based company.  With the recent $16.4M cash infusion by OpkoHealth it will be interesting to watch whether they can become a self-delivering RNAi trigger platform-based candidate again, or whether the claimed company growth will largely be around expanding the indications of RXI-109 to other anti-fibrotic indications, especially ocular ones.

Upcoming catalyst:

-          Presentation of phase I data from RXI-109 (any day).